Mission: Our long-term goal is to understanding how genes and environment interact to influence risk of environmentally induced disease. To this end we are engaged in "Environmental Genomics." This encompasses: 1) Discovery and identification of candidate environmental response genes and polymorphisms in these genes; 2) functional characterization of genetic and phenotypic variation in these genes, and; 3) the analysis in population studies of environmental disease susceptibility associated with functional polymorphisms, acquired susceptibility factors and exposures; and the interactions between these factors. Eventually we hope these genomic approaches will help us to develop assays using genotype, gene expression, and other biomarkers of exposure and effect, that will be predictive of future risk. This information will allow us to more carefully determine the bounds of human variability in risk assessment and will be useful in developing prevention strategies to reduce disease incidence. Our intention is to develop an integrated set of predictive (genotype and gene expression) assays in our groups of cell lines that will be appropriate for use in human population studies. This requires discovery of inherited and acquired risk factors and their characterization. In order to determine if genotypic and phenotypic characteristics are associated with risk of disease we will eventually test such assays in human populations with exposures to environmental agents. This would be accomplished through our collaborations with epidemiology groups at NIH and around the world. This information would have direct use in human risk assessment of chemicals. Identification of candidate genes and phenotypic differences in response to exposure. We are exposing human cell lines to various environmental agents (H2O2, and arsenic) and using gene expression profiling we are identifying exposure-inducible genes and phenotypic differences in sensitivity/resistance to exposure. The new candidate exposure-response genes are analyzed for polymorphisms (resequencing). We have identified numerous new polymorphisms in this way and are determining their functional relationship to toxicity (project 2). Identifying polymorphisms in exposure-induced genes. We developed bioinformatics methods to categorize SNPs in specific DNA sequence motifs. In our bioinformatics project we use these methods to identify polymorphic promoter response elements in candidate environmental response genes (see p53 project). If practical, the effects of these SNPs are then evaluated in functional assays. In addition, we are examining the relationship between genetic variation and variation in exposure-induced gene expression profiles. We have established proof of principal by comparing the response to exposure in cell lines that carry known polymorphisms in various environmental response genes. For example we have observed differences in BPDE-induced expression profiles between these human cell lines and through sequencing, genotyping and functional analysis, have confirmed that these expression profile differences have a genetic basis. The long range goal of our group is to translate our basic research in genetic variation, gene regulation, gene expression, and toxicological mechanisms into predictive assays that are appropriate for use in human population studies. We hope to eventually identify patterns of gene polymorphism and gene expression that will be characteristic of inherited or acquired risk status. This "discovery" project produces techniques, descriptive genomic information and leads that need to be validated and verified using functional genomics approaches and population studies. Results from this discovery phase project are not always inherently publishable, and may require extensive follow up.